Determinants of treatment-related paradoxical reactions during anti-tuberculosis therapy: a case control study

BACKGROUND: Inflammatory response following initial improvement with anti-tuberculosis (TB) treatment has been termed a paradoxical reaction (PR). HIV co-infection is a recognised risk, yet little is known about other predictors of PR, although some biochemical markers have appeared predictive. We report our findings in an ethnically diverse population of HIV-infected and uninfected adults. METHODS: Prospective and retrospective clinical and laboratory data were collected on TB patients seen between January 1999-December 2008 at four UK centres selected to represent a wide ethnic and socio-economic mix of TB patients. Data on ethnicity and HIV status were obtained for all individuals. The associations between other potential risk factors and PR were assessed in a nested case-control study. All PR cases were matched two-to-one to controls by calendar time and centre. RESULTS: Of 1817 TB patients, 82 (4.5 %, 95 % CI 3.6-5.5 %) were identified as having a PR event. The frequency of PR was 14.4 % (18/125; 95 % CI 8.2-20.6 %) and 3.8 % (64/1692; 2.9-4.7) for HIV-positive and HIV-negative individuals respectively. There were no differences observed in PR frequency according to ethnicity, although the site was more likely to be pulmonary in those of black and white ethnicity, and lymph node disease in those of Asian ethnicity. In multivariate analysis of the case-control cohort, HIV-positive patients had five times the odds of developing PR (aOR = 5.05; 95 % CI 1.28-19.85, p = 0.028), whilst other immunosuppression e.g. diabetes, significantly reduced the odds of PR (aOR = 0.01; 0.00-0.27, p = 0.002). Patients with positive TB culture had higher odds of developing PR (aOR = 6.87; 1.31-36.04, p = 0.045) compared to those with a negative culture or those in whom no material was sent for culture. Peripheral lymph node disease increased the odds of a PR over 60-fold 4(9.60-431.25, p < 0.001). CONCLUSION: HIV was strongly associated with PR. The increased potential for PR in people with culture positive TB suggests that host mycobacterial burden might be relevant. The increased risk with TB lymphadenitis may in part arise from the visibility of clinical signs at this site. Non-HIV immunosuppression may have a protective effect. This study highlights the difficulties in predicting PR using routinely available demographic details, clinical symptoms or biochemical markers

Treatment outcome of extra-pulmonary tuberculosis in Finland: a cohort study

<p>Abstract</p> <p>Background</p> <p>We investigated the treatments given, the outcome and the patient- and treatment-system dependent factors affecting treatment outcome in a national two-year cohort of culture-verified extra-pulmonary tuberculosis cases in Finland.</p> <p>Methods</p> <p>Medical records of all cases in 1995 - 1996 were abstracted to assess treatment and outcome, using the European recommendations for outcome monitoring. For risk factor analysis, outcome was divided into three groups: favourable, death and other unfavourable. Predictors of unfavourable outcome were assessed in univariate and multivariate analysis.</p> <p>Results</p> <p>In the study cohort of 276 cases, 116 (42.0%) were men and 160 (58.0%) women. The mean age was 65.7 years. A favourable outcome was achieved in 157/276 (56.9%) cases, consisting of those cured (8.0%) and treatment completed (48.9%). Death was the outcome in 17.4% (48/276) cases, including cases not treated. Other unfavourable outcomes took place in 45 (16.3%) cases. Significant independent risk factors for death in multinomial logistic regression model were male sex, high age, immunosuppression, any other than a pulmonary specialty being responsible at the end of the treatment and other than standard combination of treatment. For other unfavourable treatment outcomes, significant risk factor was treatment with INH + RIF + EMB/SM. Deep site of TB was inversely associated with the risk of other unfavourable outcome.</p> <p>Conclusions</p> <p>The proportion of favourable outcome was far below the goal set by the WHO. Age and comorbidities, playing an important role in treatment success, are not available in routine outcome data. Therefore, comparisons between countries should be made in cohort analyses incorporating data on comorbidities.</p

Rapid Molecular Detection of Rifampicin Resistance Facilitates Early Diagnosis and Treatment of Multi-Drug Resistant Tuberculosis: Case Control Study

Multi-drug resistant tuberculosis (MDR-TB) is a major public health concern since diagnosis is often delayed, increasing the risk of spread to the community and health care workers. Treatment is prolonged, and the total cost of treating a single case is high. Diagnosis has traditionally relied upon clinical suspicion, based on risk factors and culture with sensitivity testing, a process that can take weeks or months. Rapid diagnostic molecular techniques have the potential to shorten the time to commencing appropriate therapy, but have not been put to the test under field conditions.This retrospective case-control study aimed to identify risk factors for MDR-TB, and analyse the impact of testing for rifampicin resistance using RNA polymerase B (rpoB) mutations as a surrogate for MDR-TB. Forty two MDR-TB cases and 84 fully sensitive TB controls were matched by date of diagnosis; and factors including demographics, clinical presentation, microbiology findings, management and outcome were analysed using their medical records. Conventionally recognised risk factors for MDR-TB were absent in almost half (43%) of the cases, and 15% of cases were asymptomatic. A significant number of MDR-TB cases were identified in new entrants to the country. Using rpoB mutation testing, the time to diagnosis of MDR-TB was dramatically shortened by a median of 6 weeks, allowing patients to be commenced on appropriate therapy a median of 51days earlier than those diagnosed by conventional culture and sensitivity testing.MDR-TB is frequently an unexpected finding, may be asymptomatic, and is particularly prevalent among TB infected new entrants to the country. Molecular resistance testing of all acid fast bacilli positive specimens has the potential to rapidly identify MDR-TB patients and commence them on appropriate therapy significantly earlier than by conventional methods

Risk factors for poor tuberculosis treatment outcome in Finland: a cohort study

<p>Abstract</p> <p>Background</p> <p>We investigated the patient- and treatment-system dependent factors affecting treatment outcome in a two-year cohort of all treated culture-verified pulmonary tuberculosis (TB) cases to establish a basis for improving outcomes.</p> <p>Methods</p> <p>Medical records of all cases in 1995 – 1996 were abstracted to assess outcome of treatment. Outcome was divided into three groups: favourable, death and other unfavourable. Predictors of unfavourable outcome were assessed in univariate and multivariate analysis.</p> <p>Results</p> <p>Among 629 cases a favourable outcome was achieved in 441 (70.1%), 17.2% (108) died and other unfavourable outcome took place in 12.7% (80). Significant independent risk factors for death were male sex, high age, non-HIV -related immunosuppression and any other than a pulmonary specialty being responsible for stopping treatment. History of previous tuberculosis was inversely associated with the risk of death. For other unfavourable treatment outcomes, significant risk factors were pause(s) in treatment, treatment with INH+RIF+EMB/SM, and internal medicine specialty being responsible at the end of the treatment.</p> <p>Conclusion</p> <p>We observed a significant association with unfavourable outcome for the specialty responsible for treatment being other than pulmonary, but not for the volume of cases, which has implications for system arrangements. Poor outcomes associated with immunosuppression and advanced age, with frequent comorbidity, stress a low threshold of suspicion, availability of rapid diagnostics, and early empiric treatment as probable approaches in attempting to improve treatment outcomes in countries with very low incidence of TB.</p

Screening for latent TB, HIV, and hepatitis B/C in new migrants in a high prevalence area of London, UK: a cross-sectional study.

BACKGROUND: Rising rates of infectious diseases in international migrants has reignited the debate around screening. There have been calls to strengthen primary-care-based programmes, focusing on latent TB. We did a cross-sectional study of new migrants to test an innovative one-stop blood test approach to detect multiple infections at one appointment (HIV, latent tuberculosis, and hepatitis B/C) on registration with a General Practitioner (GP) in primary care. METHODS: The study was done across two GP practices attached to hospital Accident and Emergency Departments (A&E) in a high migrant area of London for 6 months. Inclusion criteria were foreign-born individuals from a high TB prevalence country (>40 cases per 100,000) who have lived in the UK ≤ 10 years, and were over 18 years of age. All new migrants who attended a New Patient Health Check were screened for eligibility and offered the blood test. We followed routine care pathways for follow-up. RESULTS: There were 1235 new registrations in 6 months. 453 attended their New Patient Health Check, of which 47 (10.4%) were identified as new migrants (age 32.11 years [range 18-72]; 22 different nationalities; time in UK 2.28 years [0-10]). 36 (76.6%) participated in the study. The intervention only increased the prevalence of diagnosed latent TB (18.18% [95% CI 6.98-35.46]; 181.8 cases per 1000). Ultimately 0 (0%) of 6 patients with latent TB went on to complete treatment (3 did not attend referral). No cases of HIV or hepatitis B/C were found. Foreign-born patients were under-represented at these practices in relation to 2011 Census data (Chi-square test -0.111 [95% CI -0.125 to -0.097]; p < 0.001). CONCLUSION: The one-stop approach was feasible in this context and acceptability was high. However, the number of presenting migrants was surprisingly low, reflecting the barriers to care that this group face on arrival, and none ultimately received treatment. The ongoing UK debate around immigration checks and charging in primary care for new migrants can only have negative implications for the promotion of screening in this group. Until GP registration is more actively promoted in new migrants, a better place to test this one-stop approach could be in A&E departments where migrants may present in larger numbers

Microneedle Array Design Determines the Induction of Protective Memory CD8+ T Cell Responses Induced by a Recombinant Live Malaria Vaccine in Mice

BACKGROUND: Vaccine delivery into the skin has received renewed interest due to ease of access to the immune system and microvasculature, however the stratum corneum (SC), must be breached for successful vaccination. This has been achieved by removing the SC by abrasion or scarification or by delivering the vaccine intradermally (ID) with traditional needle-and-syringes or with long microneedle devices. Microneedle patch-based transdermal vaccine studies have predominantly focused on antibody induction by inactivated or subunit vaccines. Here, our principal aim is to determine if the design of a microneedle patch affects the CD8(+) T cell responses to a malaria antigen induced by a live vaccine. METHODOLOGY AND FINDINGS: Recombinant modified vaccinia virus Ankara (MVA) expressing a malaria antigen was percutaneously administered to mice using a range of silicon microneedle patches, termed ImmuPatch, that differed in microneedle height, density, patch area and total pore volume. We demonstrate that microneedle arrays that have small total pore volumes induce a significantly greater proportion of central memory T cells that vigorously expand to secondary immunization. Microneedle-mediated vaccine priming induced significantly greater T cell immunity post-boost and equivalent protection against malaria challenge compared to ID vaccination. Notably, unlike ID administration, ImmuPatch-mediated vaccination did not induce inflammatory responses at the site of immunization or in draining lymph nodes. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that the design of microneedle patches significantly influences the magnitude and memory of vaccine-induced CD8(+) T cell responses and can be optimised for the induction of desired immune responses. Furthermore, ImmuPatch-mediated delivery may be of benefit to reducing unwanted vaccine reactogenicity. In addition to the advantages of low cost and lack of pain, the development of optimised microneedle array designs for the induction of T cell responses by live vaccines aids the development of solutions to current obstacles of immunization programmes

The effects of interleukin-8 on airway smooth muscle contraction in cystic fibrosis

<p>Abstract</p> <p>Background</p> <p>Many cystic fibrosis (CF) patients display airway hyperresponsiveness and have symptoms of asthma such as cough, wheezing and reversible airway obstruction. Chronic airway bacterial colonization, associated with neutrophilic inflammation and high levels of interleukin-8 (IL-8) is also a common occurrence in these patients. The aim of this work was to determine the responsiveness of airway smooth muscle to IL-8 in CF patients compared to non-CF individuals.</p> <p>Methods</p> <p>Experiments were conducted on cultured ASM cells harvested from subjects with and without CF (control subjects). Cells from the 2^ndto 5^thpassage were studied. Expression of the IL-8 receptors CXCR1 and CXCR2 was assessed by flow cytometry. The cell response to IL-8 was determined by measuring intracellular calcium concentration ([Ca²⁺]_i), cell contraction, migration and proliferation.</p> <p>Results</p> <p>The IL-8 receptors CXCR1 and CXCR2 were expressed in both non-CF and CF ASM cells to a comparable extent. IL-8 (100 nM) induced a peak Ca²⁺release that was higher in control than in CF cells: 228 ± 7 versus 198 ± 10 nM (p < 0.05). IL-8 induced contraction was greater in CF cells compared to control. Furthermore, IL-8 exposure resulted in greater phosphorylation of myosin light chain (MLC₂₀) in CF than in control cells. In addition, MLC₂₀expression was also increased in CF cells. Exposure to IL-8 induced migration and proliferation of both groups of ASM cells but was not different between CF and non-CF cells.</p> <p>Conclusion</p> <p>ASM cells of CF patients are more contractile to IL-8 than non-CF ASM cells. This enhanced contractility may be due to an increase in the amount of contractile protein MLC₂₀. Higher expression of MLC₂₀by CF cells could contribute to airway hyperresponsiveness to IL-8 in CF patients.</p

Audiologic monitoring of multi-drug resistant tuberculosis patients on aminoglycoside treatment with long term follow-up

<p>Abstract</p> <p>Background</p> <p>Multi-drug resistant tuberculosis has emerged as a significant problem with the resurfacing of tuberculosis and thus the need to use the second line drugs with the resultant increased incidence of adverse effects. We discuss the effect of second line aminoglycoside anti-tubercular drugs on the hearing status of MDR-TB patients.</p> <p>Methods</p> <p>Sixty four patients were put on second line aminoglycoside anti-TB drugs. These were divided into three groups: group I, 34 patients using amikacin, group II, 26 patients using kanamycin and group III, 4 patients using capreomycin.</p> <p>Results</p> <p>Of these, 18.75% of the patients developed sensorineural hearing loss involving higher frequencies while 6.25% had involvement of speech frequencies also. All patients were seen again approximately one year after aminoglycoside discontinuation and all hearing losses were permanent with no threshold improvement.</p> <p>Conclusion</p> <p>Aminoglycosides used in MDR-TB patients may result in irreversible hearing loss involving higher frequencies and can become a hearing handicap as speech frequencies are also involved in some of the patients thus underlining the need for regular audiologic evaluation in patients of MDR-TB during the treatment.</p

Seasonality in pulmonary tuberculosis among migrant workers entering Kuwait

<p>Abstract</p> <p>Background</p> <p>There is paucity of data on seasonal variation in pulmonary tuberculosis (TB) in developing countries contrary to recognized seasonality in the TB notification in western societies. This study examined the seasonal pattern in TB diagnosis among migrant workers from developing countries entering Kuwait.</p> <p>Methods</p> <p>Monthly aggregates of TB diagnosis results for consecutive migrants tested between January I, 1997 and December 31, 2006 were analyzed. We assessed the amplitude (<it>α</it>) of the sinusoidal oscillation and the time at which maximum (<it>θ</it>°) TB cases were detected using Edwards' test. The adequacy of the hypothesized sinusoidal curve was assessed by <it>χ</it>²goodness-of-fit test.</p> <p>Results</p> <p>During the 10 year study period, the proportion (per 100,000) of pulmonary TB cases among the migrants was 198 (4608/2328582), (95% confidence interval: 192 – 204). The adjusted mean monthly number of pulmonary TB cases was 384. Based on the observed seasonal pattern in the data, the maximum number of TB cases was expected during the last week of April (<it>θ</it>° = 112°; <it>P </it>< 0.001). The amplitude (± se) (<it>α </it>= 0.204 ± 0.04) of simple harmonic curve showed 20.4% difference from the mean to maximum TB cases. The peak to low ratio of adjusted number of TB cases was 1.51 (95% CI: 1.39 – 1.65). The <it>χ</it>²goodness-of-test revealed that there was no significant (<it>P </it>> 0.1) departure of observed frequencies from the fitted simple harmonic curve. Seasonal component explained 55% of the total variation in the proportions of TB cases (100,000) among the migrants.</p> <p>Conclusion</p> <p>This regularity of peak seasonality in TB case detection may prove useful to institute measures that warrant a better attendance of migrants. Public health authorities may consider re-allocation of resources in the period of peak seasonality to minimize the risk of <it>Mycobacterium tuberculosis </it>infection to close contacts in this and comparable settings in the region having similar influx of immigrants from high TB burden countries. Epidemiological surveillance for the TB risk in the migrants in subsequent years and required chemotherapy of detected cases may contribute in global efforts to control this public health menace.</p